Submissions for variant NM_000527.5(LDLR):c.1817C>A (p.Ala606Asp)

gnomAD frequency: 0.00001  dbSNP: rs1410295777

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000508835	SCV002506392	uncertain significance	Hypercholesterolemia, familial, 1	2022-02-10	reviewed by expert panel	curation	The NM_000527.5 (LDLR): c.1817C>A (p.Ala606Asp) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 Met: PopMax MAF = 0.00002637in European (non-Finnish) population in gnomAD (gnomAD v2.1.1). PP3 Met: REVEL = 0.756, which is above the threshold of 0.75. There are two other variants in same codon: LDLR: NM_000527:c1816G>T (p.Ala606Ser), LDLR: NM_000527:c.1816G>A (p.Ala606Thr), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865664	SCV002221135	pathogenic	Familial hypercholesterolemia	2024-04-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 606 of the LDLR protein (p.Ala606Asp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with LDLR-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 440663). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Ala606 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002413393	SCV002714123	uncertain significance	Cardiovascular phenotype	2022-03-31	criteria provided, single submitter	clinical testing	The p.A606D variant (also known as c.1817C>A), located in coding exon 12 of the LDLR gene, results from a C to A substitution at nucleotide position 1817. The alanine at codon 606 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration was detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001865664	SCV004359043	uncertain significance	Familial hypercholesterolemia	2023-05-03	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala585Asp in the mature protein) replaces alanine with aspartic acid at codon 606 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 17094996). This variant has been identified in 3/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000508835	SCV004822504	uncertain significance	Hypercholesterolemia, familial, 1	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ala585Asp in the mature protein) replaces alanine with aspartic acid at codon 606 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 17094996). This variant has been identified in 3/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508835	SCV000606522	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research